The long-term objective of this project is to better understand the role of genetic factors in the pathogenesis of pulmonary arterial hypertension (PAH), which is an autosomal dominant fatal disease. Mutations in the bone morphogenic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor (TGF-) superfamily, are found in the majority of cases of the heritable type of PAH (HPAH). A striking feature of HPAH is its incomplete penetrance-a majority of pathogenic mutation carriers (~80%) show no clinical symptoms but can produce offspring that are affected by HPAH. Thus a mutation carrier cannot predict whether he or she will develop clinical disease, creating anxiety on the mutation carrier's part and uncertainty as to treatment and follow up on the physician's part. Our proposal is designed to address this key issue in HPAH. Our data suggest a paradigm-shifting concept for HPAH pathogenesis-that expression levels of the wild-type (WT) non-mutated BMPR2 allele may be the primary determinant of disease penetrance in HPAH. This highlights the importance of BMPR2 expression in PAH pathogenesis and emphasizes the need for better understanding of mechanisms that control BMPR2 expression. Based on these data we hypothesize that disease is linked to the expression level of the WT BMPR2 allele in HPAH and total BMPR2 expression in idiopathic (I) PAH. The proposed research is a collaboration between geneticists, basic scientists, statisticians and pulmonologists and will produce a synergistic effect that is not easily matched by a single investigator. The rationale for the proposed research is that understanding the genetic mechanisms behind BMPR2 gene regulation could lead to better diagnosis and treatment options for HPAH. Our specific aims are as follows. 1. Determine the role of BMPR2 expression in disease penetrance in HPAH and as a risk factor in IPAH. 2. Determine the genomic and molecular basis of the observed variability in BMPR2 expression in HPAH and IPAH patients. 3. Identify potential new PAH treatments. This proposal is designed to be translational in nature. It presents an innovative paradigm that integrates clinical and genetic data and state of the art approaches such as quantitative trait locus mapping and the use of the Connectivity Map database to answer key unknowns in HPAH and uses that information to identify potential therapeutic targets. It is our expectation that we will: 1) develop a better understanding of the genetic factors that control BMPR2 expression; 2) develop a predictive model of disease that will have clinical diagnostic utility; and 3) identify new treatment options for PAH.